Journal
COMMUNICATIONS BIOLOGY
Volume 1, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-018-0178-4
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Funding
- National Institutes of Health [R01DE10742, R21DE023298, R01DE026304, R01CA220693, P30CA033572]
- Ministry of Science and Technology [107-2320-B-038-055-MY3, 105-2320-B-038-071-MY3]
- TMU Research Center of Cancer Translational Medicine by the Featured Areas Research Center Program/Higher Education Sprout Project
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Defective arginine synthesis, due to the silencing of argininosuccinate synthase 1 (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, arginine starvation induces asparagine synthetase (ASNS), depleting these cancer cells of aspartate, and disrupting their malate-aspartate shuttle. Supplementation of aspartate, depletion of mitochondria, and knockdown of ASNS all protect the arginine-starved cells, establishing the causal effects of aspartate depletion and mitochondrial dysfunction on the arginine starvation-induced cell death. Furthermore, dietary arginine restriction reduced tumor growth in a xenograft model of ASS1-deficient breast cancer. Our data challenge the view that ASNS promotes homeostasis, arguing instead that ASNS-induced aspartate depletion promotes cytotoxicity, which can be exploited for anticancer therapies.
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